Prostate cancer (PCa) is a leading cause of cancer death of men in the United States and Europe. Androgen therapy is the treatment of choice in men with metastatic disease. However, most patients develop androgen-insensitivity and chemoresistance, and die within a few years (1). Therefore, alternative strategies for prevention and treatment of PCa metastasis are urgently needed.
Cancer metastasis involves a series of steps such as angiogenesis, detachment of a metastatic cell from the primary tumor, intravasation, evasion of host defense, arrest at a distant site, attachment, extravasation, dormant survival, and establishment of new growth. During extravasation, cancer cells bind to endothelial cells through protein-carbohydrate interactions and penetrate through the endothelium and basement membrane (2). Thus, tumor-endothelial interaction and angiogenesis are considered key steps prior to cancer metastasis (2). Disruption of such interactions (5) may effectively prevent metastasis.
It has been demonstrated that Thomsen-Friedenreich (TF) antigen (Galβ1-3GalNAcα1-Ser/Thr) is expressed by carcinomas (3). The TF antigen (also known as CD176) is present in the core I structure of mucin-type O-linked glycan. It is generally masked by sialic acid in normal cells, but it is exposed or non-sialylated in malignant and premalignant epithelia (3). Increased surface expression of TF antigen is associated with poorer prognosis in ovarian, lung, gastric, colon, breast, and prostate cancers, implying that TF antigen is involved in cancer progression and metastasis (3).
It has been shown that endothelial cell-expressed galectin gal3 participates in docking of cancer cells including breast and prostate cancers by specifically interacting with cancer cell-associated TF disaccharide (TFD, Galβ1,3GalNAc) (4). It has further been shown that cell surface TFD mediates homotypic cell adhesion by binding to circulating gal3 (5), although other interactions could be involved. The significance of gal3-TFD interactions in mediating homotypic and heterotypic cell-cell interactions was also demonstrated by using three-dimensional co-cultures of endothelial and epithelial cells (6). Intracellular gal3 enhances mitochondrial stability and inhibits apoptosis in PCa cells in presence of certain chemotherapeutics (13). Other studies have shown that extracellular gal3 is involved in tumor cell adhesion (14). In addition to both intracellular and extracellular functions, tumor-secreted gal3 induces apoptosis of infiltrating T cells, thus acting as double-edged sword to evade immune surveillance during tumor progression (15-17).
Although several plant lectins such as peanut agglutinin (PNA), jack fruit lectin (jacalin) and Amaranthus caudatus lectin can bind to TFD (7, 8), only three mammalian lectins (gal3, gal4, and gal9) are known to interact with TFD (9, 10). These galectins can also bind N-acetyllactosamine and other N-glycans (7, 8), which may be relevant in cancer progression (11). The basis for the variable binding profiles of these galectins has been explained by their 3-D structures (9, 10, 12). Both gal4 and gal9 seem to have some roles in cancer progression (11), but it is not known if they participate through the TFD binding.
Therapeutic compositions and methods of suppressing cancer metastasis might be developed based on the interactions between TFD and galectins such as gal3.